Pavelka Z, Zitterbart K, Nosková H, Bajčiová V, Slabý O, Štěrba J
Klin Onkol. 2019 Winter;32(1):70-74. doi: 10.14735/amko201970.
Individuals with constitutional mismatch repair-deficiency syndrome (CMMR-D) are characterised by early occurrence of colon cancer, haematological malignancies, and brain tumors (malignant gliomas, high-grade gliomas) in childhood, adolescence, and early adulthood. High mutational tumor burden is typical of glioblastoma in CMMR-D patients and could be a reason why this type of glioblastoma responds well to immunotherapies, including those that employ checkpoint inhibitors.
We describe a case of an adolescent with CMMR-D that had been genetically proven by whole exome sequencing (c.2T>A/p.M1K and c.2521delT/p.W841fs PMS2 gene mutation). The patient presented successively with colon cancer and glioblastoma with a high mutational burden. The individualized glioblastoma therapy was based on the biological tumor profile and included immunotherapy with a combination of vaccination with autologous dendritic cells producing IL-12 and nivolumab, in addition to radiotherapy with metronomic temozolomide. The patient is still alive 21 months after the initial glioblastoma diagnosis and shows a complete therapeutic response documented by repeated magnetic resonance examinations.
Individuals with CMMR-D should be regularly examined using established algorithms. Whole body magnetic resonance imaging can play a key role, because it enables the early diagnosis of malignancy during the asymptomatic period. Malignancies in CMMR-D patients usually exhibit a hypermutated genotype and respond to immunotherapy. Conventional glioblastoma therapy is only palliative. Patients can benefit from an individualized therapeutic plan based on the tumor biological profile. Extensive molecular analysis of the tumor tissue is necessary. Key words hereditary cancer predisposition syndromes - glioblastoma - whole exome sequencing - immunotherapy - vaccines - checkpoint inhibitors This study was supported by the research project of the Czech Ministry of Health AZV 16-33209A (Next generation sequencing and express profiling as diagnostic tools for personalized therapeutic plans in children with solid tumors). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 26. 9. 2018 Accepted: 18. 11. 2018.
患有先天性错配修复缺陷综合征（CMMR-D）的个体的特征是在儿童期、青春期和成年早期早期发生结肠癌、血液系统恶性肿瘤和脑肿瘤（恶性胶质瘤、高级别胶质瘤）。高突变肿瘤负荷是CMMR-D患者胶质母细胞瘤的典型特征，这可能是为什么这种类型的胶质母细胞瘤对免疫疗法（包括使用检查点抑制剂的免疫疗法）反应良好的原因。
我们描述了一例经全外显子组测序基因验证（c.2T>A/p.M1K和c.2521delT/p.W841fs PMS2基因突变）的患有CMMR-D的青少年病例。该患者先后出现结肠癌和具有高突变负荷的胶质母细胞瘤。个体化的胶质母细胞瘤治疗基于肿瘤生物学特征，除了采用节拍式替莫唑胺进行放疗外，还包括用产生IL-12的自体树突状细胞疫苗和纳武单抗联合进行免疫治疗。在最初诊断胶质母细胞瘤21个月后，该患者仍然存活，多次磁共振检查记录显示其有完全的治疗反应。
应使用既定算法对患有CMMR-D的个体进行定期检查。全身磁共振成像可发挥关键作用，因为它能够在无症状期早期诊断恶性肿瘤。CMMR-D患者的恶性肿瘤通常表现出高突变基因型并对免疫疗法有反应。传统的胶质母细胞瘤治疗仅为姑息性治疗。患者可受益于基于肿瘤生物学特征的个体化治疗方案。对肿瘤组织进行广泛的分子分析是必要的。关键词遗传性癌症易感性综合征 - 胶质母细胞瘤 - 全外显子组测序 - 免疫疗法 - 疫苗 - 检查点抑制剂 本研究得到了捷克卫生部AZV 16-33209A研究项目（下一代测序和表达谱分析作为实体瘤儿童个性化治疗方案的诊断工具）的支持。作者声明他们在研究中使用的药物、产品或服务方面没有潜在的利益冲突。编辑委员会声明该手稿符合ICMJE对生物医学论文的推荐。提交日期：2018年9月26日 接受日期：2018年11月18日
